This invention relates to novel derivatives of 1-oxo-1H-thiazolo[3,2-a]pyrimidine-2-carboxamides and their acid precursors. These amides, and in many cases their acid precursors, are useful in preventing release of allergic mediators (histamine, serotonin, SRS-A, etc.) and may be used, therefore, to treat bronchial asthma, hay fever, rhinitis, atopic dermatitis, etc., and further, are useful as antiulcer agents.
Allergic reactions, the symptoms resulting from an antigen-antibody interaction, manifest themselves in a wide variety of ways and in different organs and tissues. Common allergic disorders, for example, are allergic rhinitis, a condition characterized by seasonal or perennial sneezing, running nose, nasal congestion, with itching and congestion of eyes; hay fever, a variety of allergic rhinitis that results from hypersensitivity to grass pollens; and bronchial asthma, one of the most disabling and debilitating of allergic reactions, a disease characterized by hyper-reactivity of the bronchi on exposure to various immunogenic or nonimmunogenic stimuli, resulting in bronchospasms with wheezing, short-lived paroxysms and widespread constriction of airway passages. The mechanical obstruction to airflow in airways is generally reversed by the use of bronchodilators, which provide symptomatic relief. In contrast, antiallergy agents prevent the release of mediators of anaphylaxis from tissue stores, thereby acting in a prophylactic manner to preclude elicitation of broncho-constriction by the mediators.
Cox and co-workers, Adv. in Drug Res., 5, 115 (1970), described the pharmacology of disodium cromoglycate[1,3-bis(2-carboxycromon-5-yloxy)-2-hydroxypropane, Intal]. It is not a bronchodilator, but mediates its therapeutic effects by inhibition of release of mediators of anaphylaxis and is administered prophylactically. It suffers from lack of oral efficacy and, for optimum results, is administered by inhalation as a solid inhalant.
More recently, a variety of other antiallergy agents have been described, including N-(5-tetrazolyl)-1-oxo-1H-6-alkoxypyrimido-[1,2-a]quinoline-2-carboxamides (Kadin, U.S. Pat. No. 4,017,625), 1-oxo-1H-6-substituted-pyrimido[1,2-a]quinoline-2-carboxylic acids (Kadin, U.S. Pat. No. 4,066,766), tetrazolo[a]quinazol-5-ones (Bindra, U.S. Pat. No. 4,085,213), pyrimido[2,1-a]isoquinolines (Juby et al., U.S. Pat. No. 4,127,720), and N-(5-tetrazolyl)-4-oxo-4H-pyrimido(2,1-b)benzothiazole-3-carboxamides (Bindra and Kadin, U.S. Pat. No. 4,041,163).
Chronic gastric and duodenal ulcers, collectively known as peptic ulcers, are a common affliction for which a variety of treatments have been developed. The treatment depends upon the severity of the ulcer and may range from dietary and medical (drug) treatment to surgery. A wide variety of drugs have been used to treat ulcers; the most recent of which to gain widespread attention is carbenoxolone sodium, the disodium salt of the hemisuccinate of glycyrrhetinic acid. It is reported to prevent formation of and to accelerate healing of gastric ulcers in animals, including humans ("Carbenoxolone Sodium: A Symposium," J. M. Robson and F. M. Sullivan, Eds., Butterworths, London, 1968). However, its use is accompanied by undesirable aldosterone-like side effects, such as marked antidiuretic and sodium-retaining activity and, oftentimes, potassium loss, such that continued therapy with this agent often leads to hypertension, muscle weakness and, ultimately, congestive heart failure. More recently, a histamine receptor antagonist, cimetidine, has been introduced into medical practice. The latter compound alleviates ulcers by reducing gastric acid secretion.
A variety of other compounds have been reported to possess antiulcer activity, including 1-oxo-1H-6-piperidinopyrimino[1,2-a]quinoline-2-carboxylic esters (Kadin and Moore, U.S. Pat. No. 4,014,881), 1-oxo-1H-6-substituted-pyrimido(1,2-a)quinoline-2-carboxylic acids and esters (Kadin and Moore, U.S. Pat. No. 4,031,217), tetrazolo[a]quinazol-5-ones (Bindra, U.S. Pat. No. 4,085,213).
The amides and most of the intermediate acids of the present invention are novel compounds. The known acids are those of formula II wherein R.sub.1 and R.sub.2 are hydrogen or R.sub.1 is methyl and R.sub.2 is hydrogen [Dunwell et al., J. Chem. Soc. (C), 1971, 2094]. The corresponding ethyl esters are also known, together with the ethyl ester in which R.sub.1 is methyl and R.sub.2 is hydrogen [Dunwell et al., J. Chem. Soc. (C) 1971, 2094; Allen et al., J. Org. Chem. 24, 779 (1959)]. Neither of these publications disclose a utility for either the acids or the esters.